Immune mechanisms shape the clonal landscape during early progression of prostate cancer

Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Here we show that two types of tumor clonal landscapes emerge during early progression of prostate cancer in genetically-engineered mouse models. Using lineage tracing and single-cell transcriptomics, we find that slowly progressing tumors contain a multiclonal landscape of relatively homogenous subpopulations within a well-organized tumor microenvironment, whereas more advanced and aggressive tumors contain competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that the dominant/minor modality is associated with differential immunoediting, in which minor clones are marked by increased expression of IFN?-response genes and the T-cell activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFN? pathway can rescue minor clones from elimination. These findings suggest new immunotherapy approaches to modulate clonal fitness and tumor progression in prostate cancer. Overall design: Confetti+ cells from AP lobes of 4-weeks post-TAM Nkx3.1CreERT2/+; Ptenflox/flox; K-RasLSLG12D/+; R26r-Confetti (NPK) mice were collected via FACS. Dominant and minor clones were determined by the size of the larger patches per color. For bulk RNA-seq experiments, dominant and minor cells were used for RNA isolation. For single cell RNA-seq experiments, dominant and minor cells were used for single-cell library construction via the 10x Genomics Chromium Single Cell 3' Library & Gel Bead Kit v3 (10x Genomics).